The Amorphous Form in Drug Development 2012/PDF...The Amorphous Form in Drug Development Antonio...

The Amorphous Form in Drug Development

Antonio Giordani, PhD Director, R&D Chemistry, Drug Development & OS. Rottapharm S.p.A. Monza, Italy.

Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012. [email protected]

Crystalline & Amorphous Solids

p. 2

Crystalline Amorphous

Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012.

L. Yu. Amorphous Pharmaceutical Solids: preparation, characterization and stabilization. Adv. Drug Del. Rev., 2001, 27-42.

Higher Energy

Lower Energy

Amorphous solids are characterized by a short-range molecular order (local organization) but unlike crystalline solids they do not have a long-range order of

molecular packing.

Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012

Examples of Drugs Commercialized in the Amorphous Form

p. 3

Zafirlukast Accolate®

Astra-Zeneca

Quinapril.HCl Accupril®

Pfizer

Cefuroxime Axetil Ceftin®

GSK

Increased interest in the amorphous form due to favourable dissolution properties

Advantages in the use of the amorphous form Increased solubility enhanced

bioavailability


S

N O NH2

O

N

OO

O

N OO

O

O

O

N

O

OHO

NHO

O

N

NH

O

OO

O

NH

SO

O

The Solubility Issue

p. 4 G.L. Amidon et al.. Theoretical basis for a biopharmaceutical drug classification: correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1995, 413-420

Biopharmaceutics Classification System (BCS)

Drug absorption in the GI is controlled by diffusion through membranes and solubility/dissolution rate.

Permeability is a function of Log P (Log D) and drugs with Log P >2 are considered

highly permeable.

Solubility is defined with reference to the dose number (Do), which is the ratio of the highest

drug dose strength to the administered volume (250mL).

Do >1 : low solubility compounds Do < 1 highly soluble compounds

Over 80% of drugs are commercialized as tablets,

the oral route being the preferred administration route.


Permeability & Dissolution

p. 5

BCS Distribution of Drugs

Most commercialized drugs are high permeability drugs,

dissolution is the rate limiting step for absorption of these drugs.

The solubility issue is nowadays a common problem in drug development,

the amorphous form could represent a solution.

Often drugs with high log P and hence high permeability

are characterized by low solubility.

Biopharmaceutics Classification System (BCS)


Amorphous Atrovastatin-Ca, Solubility & Bioavailability

p. 6

Cystalline Atrovastatin Calcium

SAS precipitated amorphous

Spray dried amorphous

Dissolution Profiles of crystalline and amorphous Atrovastatin calcium

J.S. Kim et al.. Physicochemical properties and oral bioavailability of amorphous atrovastatin hemi-calcium using spraying drying and SAS processes. Int. J. Pharm., 2008, 211-219.

Plasma concentrations after amorphous and crystalline Atrovastatin calcium administration

The higher free energy of the amorphous form, the larger surface area, the lower organization of the solid state with a random orientation of the molecules which lead to the exposure of

both hydrophilic and hydrophobic groups improve wettability and solubility.

Equilibrium solubility of the crystalline compound is 0.14 mg/mL

and 0.64 mg/mL for the amorphous


Amorphous Itraconazole

p. 7

Dissolution profile at pH 1.2 of spray-dried Itraconazole (F1) and crystalline (F3)

R.S.Prasad et al . Int.J. Chem.Tech. Res.2010,2(1), 133-142.

Itraconazole is a broad spectrum antifungal agent of the triazole group, it is commercialized in the amorphous form as Sporanox capsules.

It is an extremely water insoluble product, its higher solubility is at acidic pH

and corresponds to 4 !g/mL. The amorphous product was about eight times more soluble than the crystalline

counterpart.

Itraconazole belongs to BCS class II


Itraconazole Co-crystals

p. 8 N. J. Babu, A. Nangia. Solubility advantages of Amorphous Drugs and Pharmaceutical Cocrystals. Cryst. Growth & Des., 2011, 2662-2679.

Itraconazole forms co-crystals with organic acids, such as succinic, tartaric and L-malic acid.

All the co-crystals have dissolution properties better than those of the crystalline compound.

Amorphous

Succinic Tartaric

L-Mailc


Amorphous Form: Thermodynamic Properties

p. 9 K.A. Graeser et al.. The Role of Configurational Entropy in Amorphous Systems. Pharmaceutics, 2010, 224-244.

Increased Solubility

Excess in: entropy

enthalpy

free energy

Lower Physical &

Chemical Stability

Decreasing temperature-molecular mobility R

educ

e fr

ee e

nerg

y Amorphous State

Crystallization Red

uce

mol

ecul

ar

mob

ility

Relaxation

Reduction in molecular mobility without crystalizzation

Molecular mobility is represented by the reciprocal of relaxation time Adams-Gibbs


Below Tg

Amorphous Stability: Thermodynamic and Kinetic issues

p. 10

The relaxation time is a function of the configurational entropy

Configurational Entropy Heat Capacity

Melting Entropy

Crystallization is a multi-step process:

Pre-nucleation aggregates (molcular clusters)

Formation of crystal nuclei

Crystal growth

Nucleation

Growth

Though crystallization provides a means to reduce the excess in free energy, nucleation needs to overcome a barrier of potential

Reduction in free energy due to crystallization

Molecular Mobility Tg

Entropy & conformational effects

Is it easy to reach the right conformation to crystallize ?

ΔG*

D. Zhou et al.. Physical Stability of Amorphous Pharmaceuticals: importance of configurational thermodynamic quantities and molecular mobility. J. Pharm. Sci., 2002, 1803-1872.


G

Adams-Gibbs equation

Amorphous Stability: Thermodynamic & Kinetic Properties

p. 11 K.A. Graeser et al.. Correlating Thermodynamic and Kinetic Parameters with amorphous stability.

Eu. J. Pharmaceutical science, 2009, 492-498.

Stability at 30 days of several drugs in the amorphous state

There is not a relationship between relaxation time

and stability

The reduced crystallization temperature is represented by:

Tc-Tg/Tm-Tg it allows the compounds to be represented

on a common normalized scale, expressing how far above the Tg the compound must be

heated before spontaneous crystallization occurs.

There is a relationship between the reduced temperature

and the configurational entropy


p. 12

R2

NH

O

O

OR1 R1

O

Nifedipine: R1= Me R2= NO2

Lacidipine R1=Et

R2=tButylacrylate K-channel blocker

hypertension

OH

NH

O

O

O

O

OO

O

Griseofulvin Antifungal

O

O

O

OOH

Simvastatin HMG-CoA reductasi inhib.

N

O

O

O

Cl

O

OO N

H

S

OH

O

O

Trogiltazone Type 2 diabetes

SNH

NH

O O O

Tolbutamide Type 2 diabetes

O

OH

OOH

O

Salsalate NSAID

S

N O NH2

O

N

OO

O

N OO

O

O

O

Cefuroxime axetil

Structure & Amorphous Stability

Indomethacin

Acetaminophen

Compounds with high configurational entropy barriers and low mobility are expected to give rise to more stable amorphous,

the flexibility of the molecule which may represent an entropic barrier to crystallization is an important factor for amorphous stability.


Conformational Effects & Crystallization

p. 13

L. Yu et al.. Crystallization and polymorphism of conformationally flexible molecules. Org. Proc. Res. & Dev., 2000, 4, 396.

The case of Taltirelin (Ceredist), a CNS drug

It crystallizes in two crystal forms " and #

Maruyama S., et al.. Crystallization behaviour of taltirelin polymorphs in a mixture of water and methanol. J. Crystal Growth, 2000, 239.

The conformation of each polymorph was determined by SC-XRD, the ! and " forms have quite different conformations:

Crystallization from water with methanol low concentrations leads to the !-form, at high methanol concentrations "-form is

preferred.

Thus the appropriate conformation should be present in solution to crystallize a form instead of the other If the rotational energy barrier to convert a wrong conformer into the right one is high, the crystallization is difficult.


p. 14 A.  Lerbert et al.. Molecular dynamics studies of the conformation of sorbitol. Carbohydrate Res., 2009,344(16): 229.

Conformational Effects & Amorphous Stability

OH OHOH

OH

OH

OH OHOH

OH

OH

OHOH

OH

OH

OH

OH

OHOH

OH

OH

OH

OH

Xylitol Arabitol

Mannitol Sorbitol

In the dynamic equilibrium among conformers in solution the process of crystallization must select “the right conformer”, which may not be the most abundant one in solution.

Alditols: polyols derived from carbohydrates, widely used in pharmaceutical formulations. Striking different tendency to crystallize even between isomers which differ

for the stereochemistry at one carbon.

Difficult to be crystallized Crystalline: bent-chain

conformation

Easy to be crystallized Crystalline: extended conformation

Easy to be crystallized Crystalline : extended conformation

Difficult to be crystallized Crystalline : bent-chain

conformation

Thus for alditols which easily crystallize, the conformation in the solid state corresponds to the lowest energy-conformer in solution, while for the slow crystallizing alditols (sorbitol and xylitol) the conformation in the solid state

is different from those more abundant in solution.


Glass Properties of Pentitols

p. 15 L. Carpentier et al.. Crystallization and glass properties of pentitols. J. of Thermal Analysis & Calorimetry, 2003, 577.

DSC cycle : the compound is melted (A), rapidly quenched to glass, then re-heated (B).


Amorphous Form can be prepared by several methods

p. 16

Quenching of the melt

Fast precipitation from solution

Milling

Freeze Drying

Spray Drying

Wet granulation

Drying of solvated crystals

L. Yu, Amorphous Pharmaceutical Solids: preparation, characterization and stabilization, Adv. Drug Del. Rev., 2001, 27-42


Amorphous Indomethacin

p. 17

γ-crystal form grows from the amorphous

α-crystal form grows from the amorphous

V. Andronis, G. Zografi. Crystal nucleation and growth of indomethacin polymorphs from the amorphous state. J. Non-Crystalline Solids, 2000, 236-248.

N

O

O

O

Cl

O

Amorphous indomethacin can be prepared by quenching of the melt and grinding the product to powder, by milling or by spray drying.

Amorphous Indomethacin Glass Transition Temperature is 42°C

More Stable γ-form α-form

Tm= 161°C, DHf = 110 J/g Tm =155°C, DHf = 91 J/g

Below Tg the γ-form is obtained

with a temperature dependent kinetic.

At 50°C both forms crystallize

while at 60°C the α-form is

favored


p. 18

Amorphous Threalose by Milling Milling is often used for formulation needs to reduce the particle size and

to enhance surface properties by co-milling APIs with excipients.

Milling can induce physical changes in the product, such as amorphization and mechanical induced

transition from one crystal form to another.

Piroxicam, budesonide, sucrose, lactose,

treahlose becomes partially or totally amorphous when

submitted to milling.

Trehalose ! (metastable) and " crystalline forms and a dihydrate


Amorphous treahlose Tg about 120°C

Amorphous trehalose can be obtained

by quenching of the melt or by milling of the #-form

but not by milling of the dihydrate

Amorphous treahlose dihydrate

Tg about 20°C


Amorphous α-Lactose by Milling

p. 19

The amorphous form can be obtained by milling pure α-lactose

Tg = 110°C

After milling the amorphized

α-lactose is still in the α form ( >96%)

On heating the amorphous above Tg

the β fraction increases up to 50% at 132°C, this value remains unchanged by further heating

By milling it is possible to obtain the pure α-lactose amorphous form, which cannot be obtained by quenching of melt or spray-drying which gives rise to a 50% mixture.

Amorphization during the milling is not associated to a local heating/quenching process, since temperature higher than Tg

would have triggered the mutarotation effect.


O

OH

OHOH

OHO

OH

H

OH

OHOHO

Galactose Glucose

J.F. Willart, M. Descamps. L. Yu. Solid state amoprphization of pharmaceuticals. Molecular Pharmaceutics, 2008, 905-9020.

Trehalose.2H2O: Amorphization by Desolvation

p. 20

Solvate Amorphous Desolvation

Desolvation often induces solid state transformations

Trehalose.2H2O Amorphous

Trehalose α-form

Slow Fast


α-Form

XRPD after slow and fast heating

Run 1: 1°C/min. dehydration, α-form Mp: 125°C Run 2: 10°C/min dehydration, α-form + amorphous

Run 2: 50°C/min dehydration, amorphous

DSC after slow and fast heating

In the case of mixtures annealing is a way to convert the metastable form-

alpha into the amorphous


Amorphization by Spray Drying

p. 21 M. Nystrom et al.. Fabrication of amorphous pharmaceutical material by spraying into reduced pressure. 2010, Proc Esa Ann. Meet.

M. G. Gohel et al.. Spray Drying: a Review, 2009, Pharmainfo.net

SEM of Spray-Dried Mannitol

SEM of Spray-Dried Trehalose

SEM images of the spray dried indomethacin (on the left), piroxicam (in the middle) and budesonide (on the right)

Spray Drying is one of the most used techniques for the industrial preparation of amorphous pharmaceutical solids, either as pure APIs or in a mixture with excipients or phase stabilizers.

Suitable to control properties

such as particle shape and size,

moisture content, flowability and dispersibility

Simple process which converts a fluid

(solution, a slurry, an emulsion, a gel)

into a dried particulate solid,

in one step, by spraying the fluid

into a hot drying medium


Spray Drying

p. 22

2 Feedstock 3 Dried product, 4 Drying chamber, 5 Cyclone, 6 Sterile filter for feed, 7 Two-fluid / Pressure nozzle, 8 Prefilter for atomizing air, 9 Prefilter for drying air, 10 Indirect air heater,

K. Sollohub, K. Cal. Spry Drying Technique II. Current applications in pharmaceutical technology. J Pharm. Sci., 2010, 99(2), 587-597. M. G. Gohel et al., Spray Drying: a Review, 2009, Pharmainfo.net

Atomization of the liquid into small droplets

Mixing the droplets with a heated gas stream with consequent solvent evaporation

Separation and collection of dried powder from the gas stream

Pressure nuzzle

Rotary atomizer

The Process


Amorphous Paclitaxel

p. 23 S.H. Pyo et al.. Preparation and dissolution profiles of the amorphous, dihydrated crystalline and anhydrous forms of Paclitaxel. Drying Technology, 2007, 1759-1767.

Paclitaxel is one of the most important anticancer agents.

Amorphous paclitaxel is used to increase solubility of the drug in

pharmaceutical solvents, since the drug is for parenteral formulations.


p. 24

SNH

NH

O O O

Spray Drying: Tolbutamide Solid Dispersion in HPMC

R. Chen et al.. Improved dissolution of an insoluble drug using a 4-fluid nozzle spray-drying technique. Chem.Pharm.Bull.,2004, 1066-1070.

a)  Crystalline tolbutamide (TLB) b)   HPMC d) TLB:HPMC 1: 5 suspension e) TLB:HPMC 1: 5, 3 FN, 4 FN

a)  Crystalline TLB XRPD b)   HPMC XRPD c)  TLB: HPMC 1:5 physical mixture d)   TLB:HPMC 1:5 spray drying of the suspension e)  TLB:HPMC 1:5 spry drying of the solution (3 FN) f)  TLB:HPMC 1:5 spry drying of the solution (4 FN)

The solid dispersion of a drug in a water-soluble polymeric carrier such as PVP and HPMC can improve solubility and wettability and can contribute to stabilization of the amorphous state.

The spray drying techniques are widely used for the preparation of solid dispersions.


Assessment of the amorphous: XRPD

p. 25 P. Varlashkin. Approaches to quantification of amorphous content in crystalline drug substance by XRPD. Am. Pharm Review, 2011, 22-28.


XRPD is considered the gold standard for identifying and quantifying crystalline phases in pharmaceutical products.

Crystalline compounds give rise to a powder diffraction spectrum, while pure amorphous substances give rise to a very broad peak referred to

as “halo”.

Amorphous or Nanocrystalline material?

DSC or other thermal techniques can be of help to distinguish

if amorphous or microcrystalline

Sample is constituted of a mixture of amorphous and crystalline

prepare standards of both pure amorphous and crystalline

calibration mixtures (100-10%) calibration curve

If the crystalline structure is known (SC-XRD) Rietveld Quantitative Analysis can be used.

XRPD & Stability of the Amorphous Phase: Troglitazone

p. 26

O

OH

O NH

SO

O**

N. Furuyama et al.. Do amorphous Troglitazone prepared from two diastereoisomer-pairs have the same molecular mobility and crystallization rate ? Chem. Pharm. Bull. 2011,1452-1457.

RR/SS SR/RS

Changes in XRPD pattern of amorphous Troglitazone diastereoisomers stored at 70°C, 100% RH


XRPD is a quite useful tool in the assessment of amorphous stability,

RR/SS

RS/SR

Crystalline: RR/SS couple (m.p.: 127°C) RS/SR couple (m.p.: 197°C) Amorphous: Tg about 70°C for both diastereoisomers.

The stability of each single amorphous diastereoisomer was comparatively assessed

using XRPD.

p. 27

XRPD & Stability of the Amorphous Phase : Irbesartan

G. Chawla, A.K. Bansal. Molecular Mobility and Physical Stability of Amorphous Irbesartan. Sci. Pharm. 2009, 695-709.

Amorphous Stability

at 40° C, 75% RH,

3 months


Irbesartan is an AT1 antagonist approved for the treatment of hypertension. The product, commercialized as hydrochloride

sesquihydrate, has two crystalline forms (α and β) and a relatively stable amorphous form.

p. 28

XRPD & Amorphous Form : Quinapril hydrochloride

Y. Guo, S. R. Byrn, G. Zografi. Physical characteristics and chemical degradation of amorphous quinapril hydrochloride. J. Pharm. Sci., 2000, 128-143.


Quinapril hydrochloride (Accupril, Pfizer) is an angiotensin converting enzyme (ACE) inhibitor commercialized as amorphous drug.

The amorphous form of quinapril hydrochloride is obtained by desolvation on grinding of the

acetonitrile solvate.

Assessment of thermal stability for the amorphous (80°C, 5-10 hrs) highlighted the formation of a crystalline compound which is not quinapril.

N+

O

O N

OOHOHH

N

O

O

N

OO

-HCl

- H2O

Assessment of Low Amounts of Amorphous

p. 29


There are cases where formation of amorphous is undesired.

Unintentional amorphization during drug product manufacturing can occur in routine operations such as coating, granulation, drying, milling and compression.

The presence of amorphous even in small quantities can have an impact on the drug product performance.

Salbutamol was the first selective #2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and COPD.

Only small particles (2 – 5 !m) penetrate into the lower respiratory tract.

The product performance is critically dependent on the force of adhesion which is in turn dependent on

surface properties.

Presence of the amorphous can alter the surface properties of the particle thus reducing the

effectiveness of the administration.

Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012

To detect small amounts of amorphous isothermal calorimetry is considered more appropriate

than XRPD.

Isothermal Microcalorimetry

p. 30

Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012 T. Sebhatu et al.. Assessment of the degree of disorder in crystalline solids by isothermal microcalorimetry. Int. J. Pharmaceuticas, 1994, 135.

Microcalorimetric heat flow curve for 100% Amorphous SS monitored at 57% RH

Isothermal microcalorimetry can detect and quantify small amounts of amorphous material in a crystalline drug.

Isothermal calorimetry measures heat flow as a function of time.

I: absorption of water

II: exothermic recrystallization process that is proportional to the amount of amorphous present in the sample

III: desorption of water in excess

A calibration plot is obtained adding known amount of amorphous to crystalline salbutamol sulfate

The AUC varies linearly with the amorphous content

Assessment of Amorphous Salbutamol Sulfate

p. 31 S. Gaisford et al.. Following mechanical activation of salbutamol sulphate during ball-milling

with isothermal calorimetry. Int. J. Pharmaceutics, 2010, 393, 74-78. Crystal Forms@ Bologna, the 6° Workshop on Crystal Forms; 19-21 January 2012

Salbutamol sulfate micronization

In order to assess amorphous formation during milling the samples milled up to 20 min. were

analyzed by isothermal calorimetry.

Over short milling times there was a sharp reduction in particle size with no

increase in the amorphous content, while between 5 and 20 min. milling

time the size of the particles remained relatively constant with an increase in

the amorphous content.

Assessment of Amorphous Content with DVS

p. 32 D. Burnett et al.. Characterizing amorphous materials with gravimetric vapour sorption techniques. PharmTech. April 2009.


Gravimetric vapor sorption techniques are widely used to study amorphous materials and can be successfully used to detect small (<10%) amounts of amorphous

Using octane vapour is possible to assess low

concentration of amorphous in lactose.

DVS is useful also to study moisture-induced

phase changes

Vibrational Spectroscopy & Solid State

p. 33

B. Van Eedenburgh, L.S. Taylor. Application of mid-IR spectroscopy for the characterization of pharmaceutical systems. Int. J. Pharmaceutics, 2011, 3-16.

Raman

L.S. Taylor, G. Zografi. Spectroscopic characterization of interactions between PVP and indomethacin in amorphous molecular dispersion. Pharmaceutical Research, 1997, 1691.


FT-IR

Indomethacin α-form structure

4000-400 cm-1 spectral region

FT-IR along with Raman spectroscopy belongs to the wider field of vibrational spectroscopy. These techniques are very

valuable tools to investigate the amorphous state.

FT-IR

13C ssNMR & Amorphous Fraction Assessment

p. 34


13C solid state cross polarization magic angle spinning (CPMAS) NMR is becoming a widely used technique to provide information on solid state issue due to its remarkable sensitivity.

13CssCPMAS was used to assess the amorphous fraction in crystalline-amorphous mixtures of

trehalose

R. Lefort et al.. Solid state NMR and DSC methods for quantifying the amorphous content in solid dosage forms: an application to ball-milling trehalose. Int. J. Pharmaceutics, 2004, 209-219.

After recording the reference spectra of the pure crystalline and amorphous trehalose the

broadening of the NMR lines is evaluated by the software as a function of increasing amorphous

content.

p. 35

Thank You


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